PROJECT SUMMARY Ocular inflammatory diseases are major causes of vision loss in the United States, often striking at a relatively early age. Immunosuppression is a primary therapeutic approach for severe cases. The Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study, a retrospective cohort study, has evaluated long-term mortality risks and treatment effectiveness in these patients. Among 7,957 patients who met mortality analysis eligibility criteria, of whom 936 have died over 66,802 person- years of follow-up for mortality. The study found: 1) marginally statistically significant ~2-fold higher overall and ~4-fold higher cancer mortality risk with Tumor Necrosis Factor (TNF) inhibitor therapy;2) a suggestions of increased risk of cancer mortality but not overall mortality with alkylating agents;and 3) no increased risk of overall and cancer mortality with antimetabolite, calcineurin inhibitor, and systemic corticosteroid therapy. We propose to extend the study for five years to accomplish the following aims: 1) to validate preliminary findings re: overall and cancer mortality risk with TNF inhibitor therapy and cancer mortality risk with alkylating agents;2) to evaluate cancer incidence (including non-fatal cancers) for all four classes of agents;3) to adapt statistical methodology for the problem of time-dependent confounding, allowing more useful analyses of treatment effects from observational ophthalmic data, and apply these methods to evaluate the relative likelihood of treatment success with alternative agents; and 4) to estimate the costs of alternative treatment regimens. The cohort size will be increased to ~13,907 patients observed over 130,301 person-years (~1826 deaths). The enlarged database will be linked to the National Death Index and 25 state/territory cancer registries to obtain the mortality, cancer mortality and cancer incidence outcomes. A biostatistical methodologist will generalize methods for dealing with time- dependent confounding to the paired organ setting, and apply these methods to compare the merits of alternative immunosuppressive agents. A health economist will assess relative costs of alternative therapies. The SITE Cohort provides a unique platform on which key issues regaring these important treatments can be dealt with cost- effectively.